Cortico-basal Ganglia Circuits Research Articles

Contribution of therapeutic strategies for understanding the Tourette syndrome

Motion is a behavior involving a motor act programmed and executed in a particular cognitive and emotional context. Deep structures of the brain, including the basal ganglia, appear to play a crucial role in the integration of these three kinds of cortex information (motion, cognition, emotion). Through its organization, the basal ganglia system enables learning and memorization of behavioral sequences, which can then be executed as routines. Their dysfunctions seem to be associated with many psychopathological situations. Thus, tics in Tourette's syndrome (TS) can be seen as a control routines defect that may result from wiring anomaly between the cortex and the basal ganglia. By precisely targeting deep brain circuits implicated in psychiatric disorders, deep brain stimulation (DBS) offers hope for the alleviation of severe illnesses resistant to drug therapies and provides a novel tool to investigate the neuroanatomic and physiological bases of certain disorders, including Obsessive-Compulsive Disorder (OCD) and TS, for which early results indicate positive therapeutic outcomes, even during the long-term follow-up. The pathophysiologies of OCD and of TS share dysfunctions of the associative and limbic circuits running between cortical and sub-cortical structures. Recent pathophysiological hypotheses suggest that TS symptoms result from a dysfunction of the basal ganglia circuitry, notably of the ventral striatum. These data are consistent with the supposed function of cortico-basal ganglia circuits in habit learning and routine performance of habits. Based on early reports indicating that high-frequency stimulation of structures along the cortico-basal ganglia axis might be effective in alleviating TS symptoms, DBS is being tested across the world at several nodes of this circuit, including the pallidum, and thalamus. Increasing our knowledge of the functional organization of the cortico-basal ganglia circuits and of their dysfunction in pathological repetitive behaviors would certainly contribute to better define the surgical therapeutic targets, thereby improving available treatments.

Neuroimaging of tic genesis: Present status and future perspectives

Tics are hyperkinetic movements that are distinctive by their variety in semiology and duration and by their ability to be modulated by cognitive control. They are the hallmark of Gilles de la Tourette syndrome. Despite the variety of clinical presentations in this syndrome, dysfunction of cortico-striato-pallido-thalamo-cortical networks is suggested as a core pathophysiological mechanism. We review recent structural and functional neuroimaging studies that focused on the anatomical substrate of tics and their possible genesis. These studies showed a consistent relationship between structural and functional abnormalities within motor cortico-basal ganglia circuits and occurrence of tics. The failure of top-down cortical control over motor pathways because of the atypical trajectory of brain development could be a possible mechanism of tic genesis. Occurrence of tics results in several adaptive mechanisms, including modification of cortico-striatal network activity (reduced functional activation of the primary motor cortex) and neurochemical (increased γ-aminobutyric acid concentrations in the supplementary motor area) and microstructural white matter pathways rearrangements.

Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia

Recent studies have suggested the implication of the basal ganglia in the pathogenesis of schizophrenia. To investigate this hypothesis, here we have used the ketamine model of schizophrenia to determine the oscillatory abnormalities induced in the rat motor circuit of the basal ganglia. The activity of free moving rats was recorded in different structures of the cortico-basal ganglia circuit before and after an injection of a subanesthesic dose of ketamine (10mg/kg). Spectral estimates of the oscillatory activity, phase-amplitude cross-frequency coupling interactions (CFC) and imaginary event-related coherence together with animals׳ behavior were analyzed. Oscillatory patterns in the cortico-basal ganglia circuit were highly altered by the effect of ketamine. CFC between the phases of low-frequency activities (delta, 1–4; theta 4–8Hz) and the amplitude of high-gamma (~80Hz) and high-frequency oscillations (HFO) (~150Hz) increased dramatically and correlated with the movement increment shown by the animals. Between-structure analyses revealed that ketamine had also a massive effect in the low-frequency mediated synchronization of the HFO’s across the whole circuit. Our findings suggest that ketamine administration results in an aberrant hypersynchronization of the whole cortico-basal circuit where the tandem theta/HFO seems to act as the main actor in the hyperlocomotion shown by the animals. Here we stress the importance of the basal ganglia circuitry in the ketamine model of schizophrenia and leave the door open to further investigations devoted to elucidate to what extent these abnormalities also reflect the prominent neurophysiological deficits observed in schizophrenic patients.

Functions of the cortico-basal ganglia circuits for spoken language may extend beyond emotional-affective modulation in adults.

We support Ackermann et al.'s proposal that the cortico-basal ganglia circuits may play essential roles in the evolution of spoken language. Here we discuss further evidence indicating that the cortico-basal ganglia circuits may contribute to various aspects of spoken language including planning, learning, and controlling of speech in adulthood.

Phylogenetic reorganization of the basal ganglia: A necessary, but not the only, bridge over a primate Rubicon of acoustic communication

AbstractIn this response to commentaries, we revisit the two main arguments of our target article. Based on data drawn from a variety of research areas – vocal behavior in nonhuman primates, speech physiology and pathology, neurobiology of basal ganglia functions, motor skill learning, paleoanthropological concepts – the target article, first, suggests a two-stage model of the evolution of the crucial motor prerequisites of spoken language within the hominin lineage: (1) monosynaptic refinement of the projections of motor cortex to brainstem nuclei steering laryngeal muscles, and (2) subsequent “vocal-laryngeal elaboration” of cortico-basal ganglia circuits, driven by human-specific FOXP2 mutations. Second, as concerns the ontogenetic development of verbal communication, age-dependent interactions between the basal ganglia and their cortical targets are assumed to contribute to the time course of the acquisition of articulate speech. Whereas such a phylogenetic reorganization of cortico-striatal circuits must be considered a necessary prerequisite for ontogenetic speech acquisition, the 30 commentaries – addressing the whole range of data sources referred to – point at several further aspects of acoustic communication which have to be added to or integrated with the presented model. For example, the relationships between vocal tract movement sequencing – the focus of the target article – and rhythmical structures of movement organization, the connections between speech motor control and the central-auditory and central-visual systems, the impact of social factors upon the development of vocal behavior (in nonhuman primates and in our species), and the interactions of ontogenetic speech acquisition – based upon FOXP2-driven structural changes at the level of the basal ganglia – with preceding subvocal stages of acoustic communication as well as higher-order (cognitive) dimensions of phonological development. Most importantly, thus, several promising future research directions unfold from these contributions – accessible to clinical studies and functional imaging in our species as well as experimental investigations in nonhuman primates.

Cortico-basal ganglia circuits involved in different motivation disorders in non-human primates.

The ventral striatum (VS) is of particular interest in the study of neuropsychiatric disorders. In this study, performed on non-human primates, we associated local perturbation with monosynaptic axonal tracer injection into medial, central and lateral VS to characterize anatomo-functional circuits underlying the respective expression of sexual manifestations, stereotyped behaviors and hypoactive state associated with loss of food motivation. For the three behavioral effects, we demonstrated the existence of three distinct cortico-basal ganglia (BG) circuits that were topographically organized and overlapping at some cortical (orbitofrontal cortex, anterior cingulate cortex) and subcortical (caudal levels of BG) levels, suggesting interactions between motivation domains. Briefly, erection was associated with a circuit involving the orbitofrontal cortex, medial prefrontal cortex (areas 10, 11) and limbic parts of BG, i.e. medial parts of the pallidal complex and the substantia nigra pars reticulata (SNr). Stereotyped behavior was linked to a circuit involving the lateral orbitofrontal cortex (area 12/47) and limbic parts of the pallidal complex and of the SNr, while the apathetic state was underlined by a circuit involving not only the orbital and medial prefrontal cortex but also the lateral prefrontal cortex (area 8, 45), the anterior insula and the lateral parts of the medial pallidal complex and of the ventro-medial SNr. For the three behavioral effects, the cortico-BG circuits mainly involved limbic regions of the external and internal pallidum, as well as the limbic part of the substantia nigra pars reticulata (SNr), suggesting the involvement of both direct and indirect striatal pathways and both output BG structures. As these motivation disorders could still be induced in dopamine (DA)-depleted monkeys, we suggest that DA issued from the substantia nigra pars compacta (SNc) modulates their expression rather than causes them. Finally, this study may give some insights into the structure to target to achieve therapeutic benefits from deep brain stimulation in motivation disorders.

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.

Motor-Language Coupling in Huntington's Disease Families.

Traditionally, Huntington’s disease (HD) has been known as a movement disorder, characterized by motor, psychiatric, and cognitive impairments. Recent studies have shown that motor and action–language processes are neurally associated. The cognitive mechanisms underlying this interaction have been investigated through the action compatibility effect (ACE) paradigm, which induces a contextual coupling of ongoing motor actions and verbal processing. The present study is the first to use the ACE paradigm to evaluate action–word processing in HD patients (HDP) and their families. Specifically, we tested three groups: HDP, healthy first-degree relatives (HDR), and non-relative healthy controls. The results showed that ACE was abolished in HDP as well as HDR, but not in controls. Furthermore, we found that the processing deficits were primarily linguistic, given that they did not correlate executive function measurements. Our overall results underscore the role of cortico-basal ganglia circuits in action–word processing and indicate that the ACE task is a sensitive and robust early biomarker of HD and familial vulnerability.

Striatal dopamine ramping may indicate flexible reinforcement learning with forgetting in the cortico-basal ganglia circuits.

It has been suggested that the midbrain dopamine (DA) neurons, receiving inputs from the cortico-basal ganglia (CBG) circuits and the brainstem, compute reward prediction error (RPE), the difference between reward obtained or expected to be obtained and reward that had been expected to be obtained. These reward expectations are suggested to be stored in the CBG synapses and updated according to RPE through synaptic plasticity, which is induced by released DA. These together constitute the “DA=RPE” hypothesis, which describes the mutual interaction between DA and the CBG circuits and serves as the primary working hypothesis in studying reward learning and value-based decision-making. However, recent work has revealed a new type of DA signal that appears not to represent RPE. Specifically, it has been found in a reward-associated maze task that striatal DA concentration primarily shows a gradual increase toward the goal. We explored whether such ramping DA could be explained by extending the “DA=RPE” hypothesis by taking into account biological properties of the CBG circuits. In particular, we examined effects of possible time-dependent decay of DA-dependent plastic changes of synaptic strengths by incorporating decay of learned values into the RPE-based reinforcement learning model and simulating reward learning tasks. We then found that incorporation of such a decay dramatically changes the model's behavior, causing gradual ramping of RPE. Moreover, we further incorporated magnitude-dependence of the rate of decay, which could potentially be in accord with some past observations, and found that near-sigmoidal ramping of RPE, resembling the observed DA ramping, could then occur. Given that synaptic decay can be useful for flexibly reversing and updating the learned reward associations, especially in case the baseline DA is low and encoding of negative RPE by DA is limited, the observed DA ramping would be indicative of the operation of such flexible reward learning.

Evidence for a causal inverse model in an avian cortico-basal ganglia circuit

Learning by imitation is fundamental to both communication and social behavior and requires the conversion of complex, nonlinear sensory codes for perception into similarly complex motor codes for generating action. To understand the neural substrates underlying this conversion, we study sensorimotor transformations in songbird cortical output neurons of a basal-ganglia pathway involved in song learning. Despite the complexity of sensory and motor codes, we find a simple, temporally specific, causal correspondence between them. Sensory neural responses to song playback mirror motor-related activity recorded during singing, with a temporal offset of roughly 40 ms, in agreement with short feedback loop delays estimated using electrical and auditory stimulation. Such matching of mirroring offsets and loop delays is consistent with a recent Hebbian theory of motor learning and suggests that cortico-basal ganglia pathways could support motor control via causal inverse models that can invert the rich correspondence between motor exploration and sensory feedback.

The highs and lows of beta activity in cortico-basal ganglia loops.

Oscillatory activity in the beta (13–30 Hz) frequency band is widespread in cortico-basal ganglia circuits, and becomes prominent in Parkinson's disease (PD). Here we develop the hypothesis that the degree of synchronization in this frequency band is a critical factor in gating computation across a population of neurons, with increases in beta band synchrony entailing a loss of information-coding space and hence computational capacity. Task and context drive this dynamic gating, so that for each state there will be an optimal level of network synchrony, and levels lower or higher than this will impair behavioural performance. Thus, both the pathological exaggeration of synchrony, as observed in PD, and the ability of interventions like deep brain stimulation (DBS) to excessively suppress synchrony can potentially lead to impairments in behavioural performance. Indeed, under physiological conditions, the manipulation of computational capacity by beta activity may itself present a mechanism of action selection and maintenance.

Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Synchronized neural oscillations and the pathophysiology of Parkinsonʼs disease

Developments in functional neurosurgery for movement disorders and recent advances in electrophysiological techniques have allowed important insights into the role of oscillations in corticobasal ganglia circuits, both in health and in neurological disease states. Here we review recent developments in our understanding of how abnormally synchronized oscillatory activity within the corticobasal ganglia loop may play a key role in the pathophysiology of cognitive and motor phenotypes in Parkinson's disease. Recent developments highlight the motor and non-motor roles of α, β and γ oscillations in the context of Parkinson's disease. They also emphasize the importance of oscillatory coupling between basal ganglia and cortex and draw attention to the importance of interactions between different frequency bands. Oscillatory activities across multiple frequency bands and their cross-frequency interactions within spatially segregated loops of the basal ganglia-thalamo-cortical system may relate to distinct components of clinical impairment, both motor and non-motor. It is hoped that this characterization will lead to improved interventions like deep brain stimulation, tailored to specific components of clinical impairment and their associated spatial and spectral signatures.

β Oscillation during Slow Wave Sleep and Rapid Eye Movement Sleep in the Electroencephalogram of a Transgenic Mouse Model of Huntington’s Disease

Study objectivesTo search for early abnormalities in electroencephalogram (EEG) during sleep which may precede motor symptoms in a transgenic mouse model of hereditary neurodegenerative Huntington’s disease (HD).DesignIn the R6/1 transgenic mouse model of HD, rhythmic brain activity in EEG recordings was monitored longitudinally and across vigilance states through the onset and progression of disease.Measurements and resultsMice with chronic electrode implants were recorded monthly over wake-sleep cycles (4 hours), beginning at 9–11 weeks (presymptomatic period) through 6–7 months (symptomatic period). Recording data revealed a unique β rhythm (20–35 Hz), present only in R6/1 transgenic mice, which evolves in close parallel with the disease. In addition, there was an unusual relationship between this β oscillation and vigilance states: while nearly absent during the active waking state, the β oscillation appeared with drowsiness and during slow wave sleep (SWS) and, interestingly, strengthened rather than dissipating when the brain returned to an activated state during rapid eye movement (REM) sleep.ConclusionsIn addition to providing a new in vivo biomarker and insight into Huntington's disease pathophysiology, this serendipitous observation opens a window onto the rarely explored neurophysiology of the cortico-basal ganglia circuit during SWS and REM sleep.

Neural representation of a target auditory memory in a cortico-basal ganglia pathway.

Vocal learning in songbirds, like speech acquisition in humans, entails a period of sensorimotor integration during which vocalizations are evaluated via auditory feedback and progressively refined to achieve an imitation of memorized vocal sounds. This process requires the brain to compare feedback of current vocal behavior to a memory of target vocal sounds. We report the discovery of two distinct populations of neurons in a cortico-basal ganglia circuit of juvenile songbirds (zebra finches, Taeniopygia guttata) during vocal learning: (1) one in which neurons are selectively tuned to memorized sounds and (2) another in which neurons are selectively tuned to self-produced vocalizations. These results suggest that neurons tuned to learned vocal sounds encode a memory of those target sounds, whereas neurons tuned to self-produced vocalizations encode a representation of current vocal sounds. The presence of neurons tuned to memorized sounds is limited to early stages of sensorimotor integration: after learning, the incidence of neurons encoding memorized vocal sounds was greatly diminished. In contrast to this circuit, neurons known to drive vocal behavior through a parallel cortico-basal ganglia pathway show little selective tuning until late in learning. One interpretation of these data is that representations of current and target vocal sounds in the shell circuit are used to compare ongoing patterns of vocal feedback to memorized sounds, whereas the parallel core circuit has a motor-related role in learning. Such a functional subdivision is similar to mammalian cortico-basal ganglia pathways in which associative-limbic circuits mediate goal-directed responses, whereas sensorimotor circuits support motor aspects of learning.

Protocadherin 17 Regulates Presynaptic Assembly in Topographic Corticobasal Ganglia Circuits

Highly topographic organization of neural circuits exists for the regulation of various brain functions incorticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.

Overlapping connections within the motor cortico-basal ganglia circuit: fMRI-tractography analysis

Contribution of the subcortical nuclei to the coordination of human behavior is dependent on the existence of appropriate anatomical architecture. Interpretations of available data have led to opposing 'information funneling' and 'parallel processing' hypotheses. Using motor circuit as a model, we examined whether cortico-subcortical circuits, especially cortico-basal ganglia circuits, are funneled or parallel in the control of volitional movement. Twenty-five healthy subjects underwent functional magnetic resonance imaging (fMRI). Activated clusters during self-initiated, sequential finger-to-thumb opposition movements of the left hand were identified in the bilateral supplementary motor area (SMA), right lateral premotor cortex (PM) and primary motor cortex (M1), and in the right striatum and thalamus. These functionally defined clusters were applied to probabilistic tractography based on diffusion-weighted MRI to examine patterns of connectivity. Striatal and thalamic sub-regions with high probabilities of connection to the motor cortices partially overlapped, with connection to the two premotor areas outspreading rostrally relative to M1. We suggest that, on a macroscopic anatomical level, there is overlap as well as segregation among connections of the motor cortices with the striatum and thalamus. This supports the notion that neuronal information of the motor cortices is funneled, and parallel processing is not an exclusive principle in the basal ganglia.

Stimulation of contacts in ventral but not dorsal subthalamic nucleus normalizes response switching in Parkinson's disease

Switching between responses is a key executive function known to rely on the frontal cortex and the basal ganglia. Here we aimed to establish with greater anatomical specificity whether such switching could be mediated via different possible frontal–basal-ganglia circuits. Accordingly, we stimulated dorsal vs. ventral contacts of electrodes in the subthalamic nucleus (STN) in Parkinson's patients during switching performance, and also studied matched controls. The patients underwent three sessions: once with bilateral dorsal contact stimulation, once with bilateral ventral contact stimulation, and once Off stimulation. Patients Off stimulation showed abnormal patterns of switching, and stimulation of the ventral contacts but not the dorsal contacts normalized the pattern of behavior relative to controls. This provides some of the first evidence in humans that stimulation of dorsal vs. ventral STN DBS contacts has differential effects on executive function. As response switching is an executive function known to rely on prefrontal cortex, these results suggest that ventral contact stimulation affected an executive/associative cortico-basal ganglia circuit.

Cortico-basal ganglia and cortico-cerebellar circuits in Parkinson's disease: Pathophysiology or compensation?

The basal ganglia and the cerebellum are anatomically and functionally linked to the cerebral cortex through a series of well-established circuits. The disruption of dopaminergic projections in Parkinson's disease (PD) leads to an imbalance within these circuits, leading to motor and cognitive symptoms. The cortico-cerebellar (CC) network has often been viewed as a compensatory network, helping the dysfunction of the cortico-basal ganglia (CBG) circuits in PD. However, evidence for this compensatory role is scarce; most changes in cerebellar activity could equally be attributed to pathophysiological changes underlying PD. This paper will review the anatomy, interaction and function of the CBG and CC circuits, the pathophysiological, metabolic, and functional changes observed in PD, as well as the effect of levodopa and deep brain stimulation on these changes. We will use this framework to discuss the pathophysiological and compensatory mechanisms behind CBG and CC circuit activity in PD.

Dopaminergic therapy in Parkinson's disease decreases cortical beta band coherence in the resting state and increases cortical beta band power during executive control

It is not yet well understood how dopaminergic therapy improves cognitive and motor function in Parkinson's disease (PD). One possibility is that it reduces the pathological synchronization within and between the cortex and basal ganglia, thus improving neural communication. We tested this hypothesis by recording scalp electroencephalography (EEG) in PD patients when On and Off medication, during a brief resting state epoch (no task), and during performance of a stop signal task that is thought to engage two partially overlapping (or different) frontal-basal-ganglia circuits. For resting state EEG, we measured pair-wise coherence between scalp electrodes in several frequency bands. Consistent with previous studies, in the Off medication state, those patients with the greatest clinical impairment had the strongest coherence, especially in the beta band, indicating pathological over-synchronization. Dopaminergic medication reduced this coherence. For the stop signal task, On vs. Off medication increased beta band power over right frontal cortex for successful stopping and over bilateral sensorimotor cortex for going, especially for those patients who showed greater clinical improvement. Thus, medication reduced pathological coherence in beta band at rest and increased task related beta power for two potentially dissociable cortico-basal ganglia circuits. These results support the hypothesis that dopaminergic medication in PD improves neural communication both at rest and for executive and motor function.